Ranitidine, chemically identified as N-[2-[[[5-(dimethylaminomethyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-ni tro-1,1-ethenediamine (see U.S. Pat. No. 4,128,658), is a known antagonist to histamine H.sub.2 receptors. This drug is widely used in the treatment of duodenal ulcers especially as the hydrochloride salt and in the form of tablets.
Film coating of tableted drug products is a process widely practiced in the pharmaceutical field. Typically this process involves spraying a solution or suspension of a polymeric material conventionally utilized for film coating purposes onto a tablet which is being tumbled in a stream of warm air. As the solvent evaporates the polymeric film coating is uniformly deposited on the tablet's surface. Film coating can be done in either aqueous or organic solvent systems, but aqueous systems are often preferred because they avoid the safety and environmental problems associated with many organic solvents. Film coating of ranitidine HCl tablets is utilized to mask the drug's bitter taste, to provide protection from destructive environmental elements, and for esthetic purposes. It is known that ranitidine HCl is subject to degradation upon aging and that such degradation is accelerated by heat, moisture and light; for example, see Physicians' Desk Reference, 41st ed., page 993 (1987). Further, the drug is not only extremely soluble in water (greater than 900 mg/mL at 25.degree. C.) but is also very soluble in many commonly used organic solvents. Such high solubility and propensity to degrade in the presence of heat, moisture and light have therefore made it difficult to maintain the pharmaceutical integrity of polymeric film coated ranitidine HCl tablets.
In the art of tablet film coating, conventional plasticizing agents are frequently added to the polymeric solution or suspension to improve the flexibility of the film coating and thus minimize the filling in or covering over of engraved (cut in to the surface of the tablet) or embossed (raised above the surface) indicia and designs in the tablet face. In order to significantly retard the degradation of ranitidine HCl induced by the natural heat, moisture or light factors of the environment and to successfully mask its taste, the film coating must exceed a certain minimum thickness. Without a plasticizer this thickness can not be achieved for a tablet containing ranitidine HCl without considerable loss of the definition of the indicia and designs in or on the tablets. Preservation of such engraved or embossed indicia and designs is important not only for general appearance and trade dress purposes, but more important, to meet government requirements regarding identification of drug products.
Many of the plasticizers in common use in polymeric film coatings of pharmaceutical products, for example, polyethylene glycol, propylene glycol, dibutyl sebecate, mineral oil, sesame oil and diethyl phthalate, are unacceptable for use with ranitidine HCl tablets. Such commonly used plasticizers either tend to react with ranitidine HCl or promote degradation at the tablets' surfaces, resulting in pronounced discoloration which renders the tablets unmarketable. In addition, some conventional film coating polymers are also incompatible with ranitidine HCl and thus accelerate its degradation.
U.S. Pat. No. 4,302,440 (incorporated herein by reference and referred to hereinafter as "'440") provides a review of the art of tablet film coating, and discloses a process and formulations for film coatings of aspirin using an aqueous medium of hydroxypropyl methylcellulose (HPMC). This patent recites the difficulty of using aqueous film coating media with aspirin because of aspirin's instability in water.
While '440 teaches an HPMC film coating for aspirin which incorporates as the plasticizer of choice, triacetin, it does not teach an acceptable HPMC film coating for a tablet of ranitidine HCl. The inherent problems associated with ranitidine HCl because, for example, of its high solubility in many commonly used plasticizers, are quite different from those described for aspirin in '440. Drug dissolution and subsequent migration into the plasticized polymeric film coating after film application is a serious problem with ranitidine HCl. In the case of ranitidine HCl, the phenomenon of drug migration into the film coating, unlike in the aspirin case, occurs with polymeric films deposited from either aqueous or organic systems. Furthermore, '440 addresses degradation during the actual coating process only and makes no mention of the subsequent problem of film related degradation upon aging of the tablets which is a concern in the case of ranitidine HCl.
Patent No. '440 teaches a method for preparing a thinly coated aspirin tablet having a film of hydroxypropyl methylcellulose (HPMC) which is 0.5 to 2.0% of the dry weight of the aspirin tablet core, and 15% to 25% plasticizer, based on the dry weight of the HPMC. The term "tablet core" refers to a compressed tablet prior to coating.
It has now been found that in the case of ranitidine HCl an unacceptable thin film coating would result by applying film solids at the thickness taught in '440. While '440 teaches triacetin as the plasticizer of choice for aqueous film coating of aspirin, it also teaches the use of the alternate plasticizers, such as propylene glycol and polyethylene glycols, which are unsuitable for use with ranitidine HCl because they promote degradation. Further, unlike the aspirin tablet cores described in '440, ranitidine HCl tablet cores, because of their photosensitivity should be protected from light by the use of a colorant or opacifying agent in the film coating.
In summary, while '440 teaches a plasticizer containing aqueous film coating for aspirin tablets, it does not teach one skilled in the art of film coating a suitable film formulation, aqueous or organic solvent based, for a compressed tablet core of ranitidine HCl of composition similar to that taught in U.S. Pat. No. 4,128,658.